Mast cells play an important role in many inflammatory and immunological reactions by releasing an array of mediators. The goal of our studies is to understand the intracellular signal transduction pathways that lead to the release of these molecules. In previous studies we observed that protein tyrosine phosphorylation is an early and critical signal for FceRI induced degranulation. The protein tyrosine kinase Syk was found to be tyrosine phosphorylated and activated after receptor aggregation. Syk was also shown to be essential for the receptor-induced release of inflammatory mediators. In recent studies the SH2 domain-mediated membrane translocation was found to be critical for this immune receptor mediated activation of Syk for downstream signaling events and the localization of Syk in glycosphingolipid-enriched microdomains by itself was not enough to generate or enhance signaling events. Studies on the structural basis of the activation of Syk demonstrated that the two adjacent tyrosines in the activation loop were required for downstream signaling. The kinase activity of Syk played the major role in phosphorylating these tyrosines both in vivo and in vitro. Studies with a variant of the rat basophilic leukemia cell line demonstrated that activation of the Cdc42 and/or Rac1 GTPase plays an essential role in immune receptor mediated early signaling that leads to calcium mobilization and degranulation.